The Laboratory of Genetics and Physiology explores genetic programs that control the establishment and functional differentiation of diverse cell types, including mammary epithelium, hematopoietic lineages, liver, pancreas and skin. A common denominator to these cell types is their need for cytokines to control cell proliferation, survival and differentiation and death. In particular, this laboratory investigates the Jak/Stat pathway, which is activated by a diverse set of cytokines, including interleukins, growth hormone and prolactin. Moreover, authentic biological functions of these cytokine pathways are discovered and studied through the use of experimental mouse genetics, with an emphasis on the development of the mammary gland, and more recently the hematopoietic system and pancreatic beta cells. Over the past year LGP extended its focus on genetic pathways that control key aspects of cell specification in mammary tissue. Thereby, we hope to obtain a comprehensive understanding of a developmental process emanating from the mammary stem cells and finally yielding a differentiated cell secreting milk. Past work from this laboratory has established that prolactin and epidermal growth factor ligands control proliferation and differentiation of mammary epithelium during pregnancy through the transcription factor Stat5, while IL6 and LIF control cell death during involution through Stat3. Cytokine signaling through Stat3 and Stat5 has also been linked to the function of pancreatic beta cells in tissue culture. Moreover, a role for Stat3 was proposed based on mice from which the Stat3 gene was inactivated using Cre-mediated recombination based on RIP-Cre mice. As part of our quest to understand the differential and cell-specific functions of cytokines that function through Stat transcription factors, LGP scientists inactivated both Stat3 and Stat5 in pancreatic beta cells using mice carrying floxed Stat5 genes and the RIP-Cre transgene. This published study demonstrated for the first time that the RIP-Cre transgene by itself causes glucose intolerance in mice. Therefore many of the published studies using these mice have to be taken with some caution. Because of the problems with the RIP-Cre mice, we used Pdx-1-Cre mice that are not glucose intolerant. Based on these studies we have determined that neither Stat3 nor Stat5 are required for the function of pancreatic beta cells within the mouse, findings that are in contradiction with studies in tissue culture cells. LGP has established several genetic mouse models and continues to collaborate on the functions of the transcription factor Stat5 and the cell survival factor Bcl-x in the mouse. Collaborative work published in this reporting period includes the essential roles of Bcl-x in cell survival both in liver, T cells and dendritic cells.